PAPER
Synthesis of 1,2,3-Triazole-Containing Artemisinin Dimers
IR (CHCl3): 2923, 2850 cm–1.
3177
8
Yield: 67%; white solid; mp 116.2 °C; [a]D20 +259 (c 2.5, CHCl3).
1H NMR (300 MHz, CDCl3): d = 7.53 (s, 1 H, triazole), 7.48 (s, 1
H, triazole), 5.42 (s, 1 H, H-12), 4.94 (d, J = 15.1 Hz, 1 H, H-10),
4.9 (s, 1 H, H-12¢), 4.7 (d, J = 12.5 Hz, 1 H, H-10¢), 4.37 (t, J = 6.9
Hz, 4 H, OCH2), 2.6 (m, 4 H, aliphatic chain), 2.37–1.49 (m, 24 H,
arte. aliphatic), 1.3 (s, 6 H, 3-CH3, 3¢-CH3), 1.25 (s, 12 H, aliphatic),
0.94 (d, J = 6 Hz, 6 H, 9-CH3, 9¢-CH3), 0.88 (d, J = 7.3 Hz, 6 H, 6-
CH3, 6¢-CH3).
13C NMR (75 MHz, CDCl3): d = 169.4, 145.4, 121.4, 121.3, 107.9,
102.0, 100.0, 93.6, 88.2, 84.0, 80.4, 68.6, 67.4, 67.1, 61.5, 55.5,
50.2, 50.1, 50.0, 46.7, 42.3, 35.7, 34.7, 33.2, 30.6, 30.2, 30.1, 29.0,
28.7, 28.6, 27.6, 26.5, 26.4, 26.3, 24.6, 21.6, 21.0, 20.5, 18.8, 12.4.
IR (CHCl3): 3284, 2953, 2922, 2873, 1638, 1100, 1027 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.42 (s, 1 H, H-12), 4.99 (d,
J = 3.42 Hz, 1 H, H-10), 4.32 (s, 2 H, CH2C≡CH), 2.67 (m, 1 H,
C≡CH), 2.4–1.51 (m, 12 H, arte. aliphatic), 1.44 (s, 3 H, 3-CH3),
0.96 (d, J = 5.58 Hz, 3 H, 9-CH3), 0.94 (d, J = 7.17 Hz, 3 H, 6-CH3).
13C NMR (75 MHz, CDCl3): d = 104.1, 100.6, 88.0, 81.0, 79.7,
73.9, 54.9, 52.5, 44.3, 37.4, 36.3, 34.5, 30.5, 26.1, 24.6, 24.4, 20.3,
12.8.
MS (ESI): m/z = 345 (M+ + Na).
MS (ESI): m/z = 841 (M+).
Anal. Calcd for C18H26O5: C, 67.06; H, 8.13. Found: C, 67.17; H,
8.01.
Anal. Calcd for C44H68N6O10: C, 62.82; H, 8.15; N, 9.99. Found: C,
62.45; H, 8.21; N, 9.89.
9
Yield: 65%; white solid; mp 105.8 °C; [a]D20 +213 (c 2.5, CHCl3).
11b
IR (CHCl3): 3287, 2939, 2922, 1646, 1104, 1026 cm–1.
Yield: 50%; colorless gum; [a]D20 +72.28 (c 2.35, CHCl3).
1H NMR (300 MHz, CDCl3): d = 5.47 (s, 1 H, H-12), 4.84 (d,
J = 3.3 Hz, 1 H, H-10), 3.95 (m, 2 H, CH2CH2C≡CH), 3.59 (m, 2 H,
CH2CH2C≡CH), 2.65 (m, 1 H, C≡CH), 2.49–1.48 (m, 12 H, arte. al-
iphatic), 1.44 (s, 3 H, 3-CH3), 0.96 (d, J = 6.15 Hz, 3 H, 9-CH3),
0.93 (d, J = 7.41 Hz, 3 H, 6-CH3).
13C NMR (75 MHz, CDCl3): d = 104.0, 101.9, 88.0, 81.1, 69.0,
66.2, 52.5, 44.4, 37.4, 36.4, 34.6, 34.4, 30.8, 26.1, 24.6, 24.3, 20.4,
20.0, 12.9.
IR (CHCl3): 2923, 2852, 2095 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.48 (s, 1 H, triazole), 5.42 (s, 1
H, H-12), 4.95 (d, J = 9.51 Hz, 1 H, H-10), 4.91 (s, 2 H, OCH2),
4.34 (t, J = 7.1 Hz, 2 H, CH2 triazole end), 3.28 (t, J = 6.8 Hz, 2 H,
CH2N3), 2.64 (m, 1 H, H-9), 2.3 (td, J = 3.9 Hz, 2 H, H-4), 2.05–
1.56 (m, 9 H, arte. aliphatic), 1.45 (s, 3 H, 3-CH3), 1.33 (s, 12 H, al-
iphatic chain), 0.94 (d, J = 6 Hz, 3 H, 9-CH3), 0.89 (d, J = 7.3 Hz, 3
H, 6-CH3).
13C NMR (75 MHz, CDCl3): d = 144.9, 122.2, 104.1, 101.5, 87.9,
81.1, 61.6, 52.5, 51.3, 50.1, 44.3, 37.3, 36.4, 34.5, 30.8, 30.2, 28.9,
28.8, 28.7, 26.5, 26.3, 26.1, 24.6, 24.4, 20.3, 12.9.
MS (ESI): m/z = 358.9 (M+ + Na).
Anal. Calcd for C19H28O5: C, 67.83; H, 8.39. Found: C, 66.91; H,
8.27.
MS (ESI): m/z = 518 (M+).
1,2,3-Triazole-Containing Artemisinin Dimers; General Proce-
dure
Anal. Calcd for C26H42N6O5: C, 60.21; H, 8.12; N, 16.2. Found: C,
60.11; H, 8.41; N,16.01.
Synthetic aliphatic and aromatic diazide (0.476 mmol) and artemisi-
nin-derived alkyne (0.523 mmol) were taken in CH2Cl2 and H2O (3
mL, 1:1) system in a 50 mL round-bottomed flask and stirred for 5
min. CuSO4·5H2O (1.15 mmol) and sodium ascorbate (1.46 mmol)
were added and the reaction mixture was stirred at r.t. for 12 h. The
progress of the reaction was monitored by TLC (eluent: EtOAc).
After completion of the reaction, the crude mixture was partitioned
between H2O (15 mL) and CH2Cl2 (20 mL). The aqueous layer was
extracted with EtOAc (3 × 15 mL). The combined organic phases
were dried (Na2SO4) and concentrated under reduced pressure. The
crude product was purified by preparative TLC (EtOAc).
12
Yield: 41%; colorless gum; [a]D20 +9.2 (c 1.5, CHCl3).
IR (CHCl3): 2922, 2851, 1219 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.54 (s, 1 H, triazole), 7.48 (s, 1
H, triazole), 5.26 (s, 1 H, H-12), 4.94 (d, J = 8.5 Hz, 1 H, H-10),
4.88 (s, 1 H, H-12¢), 4.66 (d, J = 12.6 Hz, 1 H, H-10¢), 4.36 (t,
J = 7.1 Hz, 4 H, OCH2), 3.57 (m, 2 H, H-9, H-9¢), 2.45 (m, 4 H, H-
4, H-4¢), 2.17–1.66 (m, 18 H, arte. aliphatic), 1.55 (s, 6 H, 3-CH3,
3¢-CH3), 1.28 (s, 18 H, aliphatic chain), 0.92 (d, J = 7.6 Hz, 6 H, 9-
CH3, 9¢-CH3, 0.87 (d, J = 6.3 Hz, 6 H, 6-CH3, 6¢-CH3).
13C NMR (75 MHz, CDCl3): d = 147.7, 145.0, 122.2, 121.6, 108.0,
99.0, 93.7, 84.1, 77.4, 77.2, 69.48, 61.6, 56.3, 50.3, 50.2, 42.3, 40.5,
34.8, 34.6, 30.3, 30.1, 29.6, 29.0, 28.6, 26.2, 26.0, 24.9, 21.0, 18.8,
12.3.
10
Yield: 36%; colorless gum; [a]D20 +45.14 (c 2.05, CHCl3).
IR (CHCl3): 2924, 1453 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.54 (s, 1 H, triazole), 7.44 (s, 1
H, triazole), 5.42 (s, 1 H, H-12), 4.93 (d, J = 15.6 Hz, 1 H, H-10),
4.89 (s, 1 H, H-12¢), 4.68 (d, J = 12.6 Hz, 1 H, H-10¢), 4.35 (m, 4 H,
OCH2), 2.64–1.70 (m, 24 H, arte. aliphatic), 1.45 (s, 6 H, 3-CH3, 3¢-
CH3), 1.25 (s, 10 H, aliphatic chain), 0.95 (d, J = 6 Hz, 6 H, 9-CH3,
9¢-CH3), 0.88 (d, J = 7.3 Hz, 6 H, 6-CH3, 6¢-CH3).
13C NMR (75 MHz, CDCl3): d = 148.1, 145.0, 122.4, 121.8, 104.1,
101.4, 87.9, 81.1, 77.2, 61.4, 56.2, 56.0, 52.4, 49.7, 49.6, 44.3, 41.0,
37.3, 36.3, 34.5, 30.7, 30.3, 29.6, 29.3, 29.2, 28.7, 26.1, 24.6, 24.4,
22.9, 20.5, 20.3, 12.9.
MS (ESI): m/z = 855 (M+).
Anal. Calcd for C45H70N6O10: C, 63.21; H, 8.25; N, 9.83. Found: C,
63.31; H, 8.20; N, 9.81.
13
Yield: 40%; colorless gum; [a]D20 +15.7 (c 1.15, CHCl3).
IR (CHCl3): 2926, 2867, 1453, 1220 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.45 (s, 1 H, triazole), 7.31 (s, 1
H, triazole), 6.2 (s, 1 H, H-12), 5.1 (s, 1 H, H-12¢), 4.77 (d, J = 4.2
Hz, 1 H, H-10), 4.75 (d, J = 4.2 Hz, 1 H, H-10¢), 4.32 (t, J = 7.17
Hz, 4 H, aliphatic chain), 3.9 (m, 4 H, CH2CH2), 3.59 (m, 2 H, H-9,
H-9¢), 2.9 (m, 4 H, OCH2CH2), 2.4–1.6 (m, 22 H, arte. aliphatic),
1.55 (s, 6 H, 3-CH3, 3¢-CH3), 1.3 (s, 12 H, aliphatic), 0.91 (d, J = 3.6
Hz, 6 H, 9-CH3, 9¢-CH3), 0.86 (d, J = 2.8 Hz, 6 H, 6-CH3, 6¢-CH3).
MS (ESI): m/z = 762.2 (M+ – 60 + Na).
Anal. Calcd for C41H62N6O10: C, 61.63; H, 7.82; N, 10.52. Found:
C, 61.61; H, 7.78; N, 10.48.
11a
Yield: 38%; colorless gum; [a]D20 +16.61 (c 0.55, CHCl3).
Synthesis 2011, No. 19, 3173–3179 © Thieme Stuttgart · New York